Safety of combined ablative radiotherapy and immune checkpoint inhibitors in three phase I trials.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI. METHODS: Patients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1-4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression. RESULTS: 213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated "possibly" related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE. CONCLUSION: This analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints.

Combined Stereotactic Body Radiation Therapy and Immune Checkpoint Inhibition for Liver Metastases: Safety and Outcomes in a Pooled Analysis of 3 Phase 1 Trials.

PURPOSE: Stereotactic body radiation therapy (SBRT) safely and effectively controls liver metastases (LMs), but its safety and efficacy when combined with immune checkpoint inhibitors (ICIs) are not well characterized. This analysis of 3 phase 1 trials of combination SBRT and ICI evaluates whether LM-SBRT increases the risk for hepatotoxicity when combined with ICI and explores efficacy endpoints. METHODS AND MATERIALS: Data were analyzed from 3 phase 1 trials of combination SBRT and ICI for patients with metastatic solid tumors conducted between 2016 and 2020. ICI was administered per trial protocol with LM-SBRT delivered to 45 Gy in 3 fractions with mean liver dose <16 Gy and ≥700 cc of normal liver spared 17.1 Gy. Hepatic adverse events (HAEs) were defined as hepatic failure, autoimmune hepatitis, or elevation of aspartate transaminase, alanine transaminase, bilirubin, or alkaline phosphatase using Common Terminology Criteria for Adverse Events version 4.0. Cumulative incidence of HAEs and local failure were modeled with death as a competing risk. Competing risk regression was performed using Fine-Gray modeling. Survival was estimated via the Kaplan-Meier method. RESULTS: Two hundred patients were analyzed, including 81 patients with LM, 57 of whom received LM-SBRT. The 12-month rate of any grade ≥2 HAE was 11% and 10% in LM-SBRT and non-LM-SBRT patients, respectively non-significant (NS). Radiographic evidence for liver disease and dual-agent ICI was significantly associated with HAEs on univariable and multivariable analysis, but liver dose metrics were not. Patients with LM had significantly worse progression-free and overall survival compared with those without, and local failure of treated LM was significantly higher than for treated extrahepatic metastases (28% vs 4% at 12 months, P < .001). CONCLUSIONS: Combination LM-SBRT and ICI did not significantly increase the risk for HAEs compared with ICI without LM-SBRT, suggesting hepatotoxicity is largely driven by factors other than liver radiation therapy, such as choice of ICI. LM is associated with worse overall survival and local control outcomes.

Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases.

BACKGROUNDWe previously demonstrated the safety of stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) in patients with advanced solid tumors. This phase I clinical trial was expanded to study the safety of partial tumor irradiation (partial-Rx). We assessed irradiated local failure (LF) and clinical outcomes with correlations to biomarkers including CD8+ T cell radiomics score (RS) and circulating cytokines.METHODSPatients received SBRT to 2-4 metastases and pembrolizumab for up to 7 days after SBRT. Tumors measuring up to 65 cc received the full radiation dose (complete-Rx), whereas tumors measuring more than 65 cc received partial-Rx. Landmark analysis was used to assess the relationship between tumor response and overall survival (OS). Multivariable analysis was performed for RS and circulating cytokines.RESULTSIn the combined (expansion plus original) cohort, 97 patients (219 metastases) were analyzed and received SBRT+P. Forty-six (47%) patients received at least 1 partial-Rx treatment. There were 7 (7.2%)dose-limiting toxicities (DLTs). 1-year LF was 7.6% overall, and 13.3% and 5.4% for partial-Rx and complete-Rx tumors, respectively (HR 2.32, 95% CI 0.90-5.97, P = 0.08). The overall, unirradiated, and irradiated objective response rates were 22%, 12%, and 34%, respectively. Irradiated tumor response to SBRT+P was associated with prolonged OS; 1-year OS was 71% (responders), 42% (mixed-responders), and 0% (nonresponders) (P < 0.01). High-RS was significantly associated with improved LF, progression-free survival (PFS), and OS. Elevated circulating IL-8 was independently associated with inferior PFS and OS.CONCLUSIONSBRT+P is safe in patients with large, advanced solid tumors. Additional studies are warranted to assess noninferiority of complete versus partial irradiation of tumors in the setting of immunotherapy.TRIAL REGISTRATIONClinicaltrials.gov NCT02608385FUNDINGMerck Investigator Studies Program; Hillman Fellows for Innovative Cancer Research Program; NIH grants UM1CA186690-06, P50CA254865-01A1, P30CA047904-32, and R01DE031729-01A1.

Predictors of Pneumonitis in Combined Thoracic Stereotactic Body Radiation Therapy and Immunotherapy.

PURPOSE: Thoracic stereotactic body radiation therapy (SBRT) is associated with high rates of local control but carries a risk of pneumonitis. Immunotherapy is a standard treatment for patients with metastatic disease but can also cause pneumonitis. To evaluate the feasibility and safety of thoracic SBRT with systemic immunotherapy, clinical outcomes of patients treated with immune checkpoint blockade (ICB) and SBRT on prospective trials were reviewed. METHODS AND MATERIALS: Three consecutive phase 1 trials of combination SBRT and ICB conducted between 2016 to 2020 for widely metastatic solid tumors were reviewed. The protocols mandated adherence to NRG BR001/BR002 organs at risk constraints, resulting in <100% coverage of some target volumes. ICB was administered either sequentially (within 7 days after completion of SBRT) or concurrently (before or at the start of SBRT), depending on protocol. End points included pneumonitis, dose-volume constraints, local failure, and overall survival. The cumulative incidence estimator and Kaplan-Meier method were used. RESULTS: In the study, 123 patients met eligibility with 311 metastases irradiated. The most common histologies included non-small cell lung cancer (33%) and colorectal cancer (12%). Median follow-up was 12 months. The overall rate of grade 3+ pneumonitis was 8.1%; 1-year local failure was 3.6%. Established dosimetric parameters were significantly associated with the development of pneumonitis (P < .05). In most patients, the lungs were not challenged with high doses of radiation, defined as receiving ≥75% of the maximum for a given lung dose-volume constraint. Patients who were challenged were not found to have a significantly higher risk of pneumonitis. CONCLUSIONS: In the largest series of thoracic SBRT and immunotherapy, local control was excellent with acceptable toxicity and support the conclusion that established dose-volume constraints for the lung are safe. However, these results highlight the potential value in reporting of organs at risk being challenged with doses approaching protocol specified limits.

Decreased overall survival in patients with locally advanced head and neck cancer receiving definitive radiotherapy and concurrent cetuximab: National Cancer Database analysis.

BACKGROUND: Recently, randomized trials have questioned the efficacy of cetuximab-based bioradiotherapy compared to chemoradiation for patients with squamous cell carcinoma of the oropharynx, larynx, and hypopharynx (HNSCC). We compared the OS of patients treated with radiotherapy alone (RTonly), chemoradiotherapy (chemoRT), and bioradiotherapy (cetuxRT). METHODS: Patients with stage III-IVB HNSCC treated with RTonly, chemoRT, or cetuxRT were identified in the National Cancer Database. OS was estimated using Cox proportional hazards. Analyses were conducted on the overall cohort and propensity matched cohorts. RESULTS: 31 014 patients were treated with RTonly (22%), chemoRT (72%), or cetuxRT (6%) from 2013 to 2016. The 2-year OS was 69% for RTonly, 79% for chemoRT, and 66% for cetuxRT (p < 0.001). In the overall and propensity-matched cohorts, chemoRT and RTonly were associated with improved OS as compared to cetuxRT (p ≤ 0.001). CONCLUSION: Compared to chemoRT or RTonly, cetuxRT is associated with decreased OS for patients with HNSCC, suggesting minimal benefit of bioradiotherapy in this population.

Impact of anatomic site of distant metastasis on survival in salivary gland cancers.

BACKGROUND: As exemplified in patients with adenoid cystic carcinoma (ACC), metastatic salivary gland cancers display heterogenous behavior. Although anatomic site of metastasis has been suggested to be prognostic for survival in this population, this is not adequately characterized in the current literature. METHODS: Using the National Cancer Database (NCDB), patients with newly diagnosed metastatic salivary gland cancers with distant metastasis to a single organ were identified. RESULTS: Eight hundred and fifty-eight patients (n = 284 bone-only, n = 322 lung-only, n = 252 other-site-only) were identified. Anatomic site of distant metastasis was not associated with survival in the cohort as a whole; however, on pre-planned subgroup analysis, lung-only metastasis, relative to bone-only metastasis, was the only factor associated with improved survival in patients with ACC (HR: 0.52, 95%CI: 0.30-0.93, p = 0.029). CONCLUSIONS: Anatomic site of metastasis is strongly associated with survival in patients with metastatic ACC and should be considered in future studies aiming to optimize therapy in this population.

Patterns of Care and Survival Outcomes for Odontogenic Cancers.

OBJECTIVES: Our understanding of odontogenic cancers is limited primarily to case studies given the rarity of these head and neck neoplasms. Using the National Cancer Database, we report the treatment patterns and survival outcomes for one of the largest cohorts of patients with odontogenic cancers. METHODS: Patients with odontogenic tumors who did not have metastatic disease and received at least part of their care at the reporting facility were included. Patient and treatment variables were assessed using logistic regression. Survival was assessed using Cox proportional hazard models. RESULTS: We identified 437 patients with odontogenic cancers, the majority of which had malignant ameloblastoma (n = 203) or odontogenic carcinoma (n = 217). Median follow-up was 44.8 months. On multivariate analysis, improved survival was associated with age <57 years (Hazard ratios [HR] 0.44, P = .012), lower comorbidity scores (HR 0.40, P = .008), surgical resection (HR 0.08, P < .001) and absence of lymph node metastasis (HR 0.23, P < .001). The 5-year overall survival was 87.1% for debulking surgery, 88.6% for radical resection and 26.6% for no surgical resection (P < .001). Lymph node metastases were associated with tumor size ≥5 cm (P = .006), malignant odontogenic histology (P = .025), and moderate/poor differentiation (P < .001). CONCLUSION: In this large series of odontogenic cancers, any type of surgical resection was associated with improved survival. Lymph node metastases, although infrequent, were associated with significantly worse survival. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 131:E1496-E1502, 2021.

A Validated T Cell Radiomics Score Is Associated With Clinical Outcomes Following Multisite SBRT and Pembrolizumab.

PURPOSE: Combining immune checkpoint blockade (ICB) with stereotactic body radiation therapy (SBRT) may improve the local response to radiation and the systemic response to immunotherapy. However, no prognostic markers exist to identify patients likely to benefit from combined therapy. The degree of T cell-mediated immunity, which can be quantified with radiomics using computed tomography (CT) imaging, is predictive of immunotherapy response. Herein we investigated whether a validated T cell radiomics score (RS) is correlated with clinical outcomes after multisite SBRT and pembrolizumab (SBRT + P). METHODS AND MATERIALS: The RS was quantified for 68 patients with metastatic treatment-refractory adult solid tumors who received SBRT (30-50 Gy, 3-5 fractions) and pembrolizumab ≤7 days after SBRT. RS was calculated using 8 variables, including 5 radiomics features extracted from pretreatment CT scans. At a prespecified cutoff of the 25th percentile, we assessed the association between RS and clinical outcomes. The Kaplan-Meier method was used to estimate survival outcomes. The prognostic effect of RS was assessed via logistic regression or Cox proportional hazards models. In an exploratory analysis, RS was also analyzed as a continuous variable. RESULTS: One hundred thirty-nine tumors were analyzed. At the 25th percentile cutoff, high-RS patients were more likely to exhibit irradiated tumor responses to SBRT + P (odds ratio [OR] 10.2; 95% confidence interval [CI], 1.76-59.17; P = .012). High-RS was associated with improved TMC compared with low-RS tumors (hazard ratio [HR] 0.18; 95% CI, 0.04-0.74; P = .018). Furthermore, high-RS patients had improved PFS (HR 0.47, 95% CI, 0.26-0.85; P = .013) and OS (HR 0.39, 95% CI, 0.20-0.75; P = .005). As a continuous variable, higher RS was associated with improved PFS (HR 0.12, 95% CI, 0.03-0.51; P = .004) but did not reach statistical significance for TMC (HR 0.36, 95% CI, 0.02-7.02; P = .502) or OS (HR 0.28, 95% CI, 0.05-1.55; P = .144). CONCLUSIONS: We demonstrated the clinical validity of RS (at the 25th percentile cutoff) as a prognostic biomarker in patients treated with SBRT + P. Future validation of the prognostic value of RS in larger similarly treated patient cohorts is warranted.

Utilizing the TrueBeam Advanced Imaging Package to monitor intrafraction motion with periodic kV imaging and automatic marker detection during VMAT prostate treatments.

BACKGROUND: Fiducial markers are frequently used before treatment for image-guided patient setup in radiation therapy (RT), but can also be used during treatment for image-guided intrafraction motion detection. This report describes our implementation of automatic marker detection with periodic kV imaging (TrueBeam v2.5) to monitor and correct intrafraction motion during prostate RT. METHODS: We evaluated the reproducibility and accuracy of software fiducial detection using a phantom with 3 implanted fiducial markers. Clinical implementation for patients with intraprostatic fiducials receiving volumetric modulated arc therapy (VMAT) utilized periodic on-board kV imaging with 10 s intervals during treatment delivery. For each image, the software automatically identified fiducial locations and determined whether their distance relative to planned locations were within a 3 mm tolerance. Motion was corrected if either ≥2 fiducials in a single image or ≥1 fiducial in sequential images were out of tolerance. RESULTS: Phantom studies demonstrated poorer performance of linear fiducials compared to collapsible fiducials, and wide variability to accurately detect fiducials across eight software settings. For any given setting, results were relatively reproducible and precise to ~0.5 mm. Across 17 patients treated with a median of 20 fractions, the software recommended a shift in 44% of fractions, and a shift was actually implemented after visual confirmation of movement greater than the 3 mm threshold in 20% of fractions. Adjustment of our approach led to improved accuracy for the latter (n = 7) patient subset. On average, table repositioning added 3.0 ± 0.3 min to patient time on table. Periodic kV imaging increased skin dose by an estimated 1 cGy per treatment arc. CONCLUSIONS: Periodic kV imaging with automatic detection of motion during VMAT prostate treatments is commercially available, and can be successfully implemented to mitigate effects of intrafraction motion with careful attention to software settings.

Patterns of Care and Outcomes of Intensity-Modulated Radiotherapy and 3D Conformal Radiotherapy for Early Stage Glottic Cancer: A National Cancer Database Analysis.

Early stage glottic cancer has traditionally been treated with 3D conformal radiotherapy (3DCRT). However, intensity-modulated radiotherapy (IMRT) has been recently adopted as an alternative to decrease toxicity. Here, we compared the usage and outcomes of IMRT and 3DCRT for patients with early stage squamous cell carcinoma (SCC) of the glottic larynx. Using the National Cancer Database, we identified patients with Stage I-II SCC of the glottis who received 55-75 Gy using IMRT (n = 1623) or 3DCRT (n = 2696). Median follow up was 42 months with a 5-year overall survival (OS) of 72%. Using a nominal logistic regression, race, ethnicity, year of diagnosis and fraction size were associated with the receipt of IMRT (p < 0.05). Using Kaplan-Meier methods and Cox proportional hazards models as well as a propensity matched cohort, there was no difference in OS for patients who received IMRT versus 3DCRT (hazard ratio (HR), 1.08; 95% confidence interval (95% CI), 0.93-1.26; p = 0.302). However, there was a survival benefit for patients receiving slight hypofractionation as compared to conventional fractionation (HR, 0.78; 95% CI, 0.69-0.92; p = 0.003). IMRT was associated with similar survival as 3DCRT, supporting the implementation of this potentially less toxic modality without compromising survival.

Concurrent chemotherapy is associated with improved survival in elderly patients with bladder cancer undergoing radiotherapy.

BACKGROUND: The current study was conducted to compare the overall survival (OS) of concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) alone in elderly patients (those aged ≥80 years) with muscle-invasive bladder cancer (MIBC). METHODS: Patients aged ≥80 years with cT2-4, N0-3, M0 transitional cell MIBC who were treated with curative RT (60-70 Gray) or CCRT were identified in the National Cancer Data Base. Univariable and multivariable frailty survival analyses, as well as 1-to-1 propensity score matching, were used to isolate the association between CCRT and OS. RESULTS: A total of 1369 patients who were treated with RT from 2004 through 2013 met eligibility criteria: 739 patients (54%) received RT alone and 630 patients (46%) received CCRT. The median age of the patients was 84 years (range, 80-90 years). The median follow-up was 21 months. The 2-year OS rate was 48%. When comparing CCRT with RT alone, the 2-year OS rate was 56% versus 42% (P<.0001), respectively. Multivariable analysis demonstrated that CCRT (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.65-0.84 [P<.0001]) and a higher RT dose (HR, 0.78; 95% CI, 0.67-0.90 [P<.001]) were associated with improved OS. T4 disease was associated with worse OS (HR, 1.42; 95% CI, 1.15-1.76 [P = .001]). After using 1-to-1 propensity score matching, there remained an OS benefit for the use of CCRT (HR, 0.77; 95% CI, 0.67-0.90 [P<.001]). CONCLUSIONS: CCRT is associated with improved OS compared with the use of RT alone in elderly patients with MIBC, independent of Charlson-Deyo comorbidity score, suggesting that CCRT should be used in this population. Cancer 2017;123:3524-31. © 2017 American Cancer Society.